Ethyl 4-trichloroacetamido-4-hexenoate

ABSTRACT

This invention relates to a novel synthesis of 4-amino-5-hexenoic acid by thermal rearrangements, and to the novel intermediates produced thereby.

CROSS-REFERENCE TO RELATED APPLICATION

This is a division, of application Ser. No. 08/279,620, filed Jul. 22,1994, now U.S. Pat. No. 5,440,065, which is a division of applicationSer. No. 08/184,762, filed Jan. 19, 1994, now which is a continuation ofapplication Ser. No. 07/986,636, filed Dec.7, 1992, now abandoned, allof which are herein incorporated by reference.

This invention relates to a novel synthesis of 4-amino5-hexenoic acidusing thermal rearrangement reactions, and to the novel intermediatesproduced thereby.

4-Amino-5-hexenoic acid, otherwise known as vigabatrin or vinyl GABA isa GABA-T inhibitor marketed under the tradename SABRIL® for thetreatment of epilepsy. (See review article on vigabatrin by S.M. Grant,et al in Drugs, 41 (6): 889-926, 1991).

In essence, this process is based upon known thermal reactions startingfrom erythritol; said thermal reactions being (1) an elimination processfor the formation of a double bond, (2) a Claisen rearrangement and (3)an Overman rearrangement. The involved reaction sequence is depicted bythe following reaction scheme. ##STR1## wherein Et is ethyl.

Step (a) of the process involves the known thermal rearrangementreaction for the preparation of 4-formyloxy-3-hydroxy-1-butene (2) fromerythritol (1) (see Prevost, C., Ann. Chem.[10 ], 10, 398, 1928).Although no work-up is necessary, better yields of a purer compound maybe obtained if the product is re-distilled. Step (b) involves a secondthermal rearrangement reaction-- followed by a hydrolysis - wherein4-formyl-3-hydroxy-1-butene is heated at 140°-150° C. in the presence ofexcess quantities of the orthoacetate (4 to 1) under conditions forremoval of the in situ produced alcohol. (See Johnson W. and Coll, J.Am. Chem. Soc.92, 741, 1970). Following hydrolysis and removal of theexcess orthoacetate, the so-produced product ethyl6-formyloxy-4-hexenoate may be used as is, or it may optionally besubjected to a distillation for purification or it may be subjected toflash chromatography on SiO₂. Alternatively this thermal rearrangementmay be effected using one equivalent of the orthoacetate in an inertsolvent which boils around 140° to 150° C. (e.g. xylene). The reactiontime for these reactions may be monitored by the measurement of thealcohol (methanol or ethanol) which is distilled off.

Step (c) involves the conversion of the formate to its correspondingalcohol by allowing the formate to be stirred at temperatures of about15° to 25° C. whilst in absolute ethanol to which catalytic quantitiesof alcoholic HCl gas has been added. Step (d) involves the reaction oftrichloroacetonitrile with ethyl 6-hydroxy-4-hexenoate in the presenceof catalytic quantities of NaH (≅0.1 equivalent) in an aprotic anhydroussolvent (preferably anhydrous ether) under an inert gas, preferablynitrogen, at about 0° C. to form an in situ imidate intermediate (5)which, by thermal rearrangement, is converted to ethyl4-trichloroacetoamido-5-hexenoate (6); the rearrangement being effectedusing the techniques of Overman, L. J., Am. Chem. Soc.98, 2901, 1976.The final step involves the hydrolysis of the imidate, preferably byacid hydrolysis but alternatively using basic hydrolysis conditions, toproduce the desired 4-amino-hexenoic acid, as its HCl salt. The freeacid or other pharmaceutically acceptable salts thereof may be obtainedby standard procedures well known in the art.

The advantages of this process may be summarized as follows:

(1) the process does not utilize or form carcinogenic materials, nor areany dangerous reactants or solvents utilized,

(2) the starting material may be prepared from an inexpensive rawmaterial (potato starch),

(3) reaction sequence may be done with only one purification before thefinal hydrolysis,

(4) a limited number of organic solvents are needed,

(5) the excess of reactants (e.g. trichloroorthoacetate) and solvents(e.g. xylene) may be recovered and re-cyclized,

(6) lack of undesirable by-products,

(7) reactions are facile without problems associated with temperaturecontrol and the products may be purified without the need forchromatographic work-up.

The following example illustrates the novel process of this invention.

EXAMPLE 1 4-Amino-5-hexenoic acid

STEP A: 4-FORMYLOXY-3-HYDROXY-1-BUTENE:

A solution of erythritol (50 g, 0.5 mole) in aqueous formic acid (150 g,75%) was heated above 100° C. , 12H, then water and formic acid weredistilled off and the reaction mixture was heated above 200° C. with aBunsen burner. The product was collected by distillation (b.p. 230° C.,30 g) and should be rectified (b.p. 90° C., 15 mn).

¹ H NMR (90 MHz) (CDCl₃, TMS)δ ppm. 3.23 (s, 1H, OH), 3.6 (m, 1H, CH),4.23 (t, 2H, CH₂), 5.33 (m, 2 H, CH₂ ═), 5.83 (m, 1H, --CH═), 8.16 (s,1H, HCO₂).

STEP B: ETHYL 6-FORMYLOXY-4-HEXENOATE:

A solution of 4- formyloxy-3-hydroxy-1-butene (1.06 g, 10 mmol) andpropionic acid (1 drop) in triethylorthoacetate (6 g, 40 mmol) washeated at 140° C. under conditions for distillative removal of ethanol.After 2H, the excess of ethylorthoacetate was removed by distillation invacuo. The residue was hydrolysed with water and extracted with AcOEt.The product was purified by flash chromatography on SiO₂ (eluant AcOEt:hexane, 2:8) (1 g, 60%) but distillative purification is preferred whenlarger quantities are involved.

¹ H NMR (90 MHz) (CDCl₃, TMS)δ ppm. 1.26 (t, 3H, CH₃, J=6 Hz), 2.4 (s,4H, (CH₂)₂), 4.1 (q, 2H, CH₂, J=6 hz), 4.6 (d, 2H, CH₂ --C═, J=6 Hz),5.73 (m, 2H, CH═CH), 8.06 (s, 1H, HCO₂).

STEP C: ETHYL 6-HYDROXY-4-HEXENOATE:

A solution of 6-formyloxy-6-hexenoate (0.9 g, 5 mmol) in absolute EtOH(10 mL) containing few drops of a saturated solution of alcoholic HCLgas was left 2H at 20° C. The solvent was removed in vacuo and theresidue was used for the next step without further purification (0.7 g,quantitative). This compound was found to be partially decomposed byflash chromatography on SiO₂. ¹ H NMR (90 MHz) (CDCl₃, TMS)δ ppm. 1.26(t, 3H, CH₃, J=6 Hz), 2.4 (s, 4H, (CH₂)₂), 2.83 (s, 1H, OH), 4.1 (s, 2H,CH₂ --C□) 4.16 (q, 2H, CH₃ CH₂, J=6 Hz), 5.7 (s, 2H, CH═CH).

STEP D: ETHYL 4-TRICHLOROACETAMIDO-5-HEXENOATE:

Sodium hydride (0.03 g of a 50% dispersion in oil, 0.5 mmol, was addedto a solution of ethyl 6-hydroxy-4-hexenoate (0.7 g, 5 mmol) andtrichloroacetonitrile (0.6 g, 5 mmol) in anhydrous ether (50 mL) underN₂ at 0° C. After 1H, ethanol (0.5 mmol) was added and the solvent wasremoved in vacuo. The formation of the imidate was controled by NMR (NH,˜8.5 ppm). A solution of the crude imidate in xylene (30 mL) was heatedat reflux 48H. Then the solvent was removed in vacuo and the residue waspurified by flash chromatography on SiO₂. (eluant AcOEt: hexane, 2:8) togive the title product (1.1 g, ˜70%). ¹ H NMR (90 MHz) (CDCl₃, TMS)δppm. 1.23 (t, 3H, CH₃, J=6 Hz), 2.0 (t, 2H, CH₂ --CH₂ --CO₂ , J=5 Hz),2.36 (s, 2H, CH₂ CO₂), 4.1 (q, 2H, CH₃ CH₂, J=6 Hz), 4.4 (t, 1H,C---CH₂, J=5 Hz), 5.1 (m, 2H, CH₂), 5.76 (m, 1H, CH═CH₂), 7.2 (s, 1H,NH).

A sample was distilled for analysis (b.p. 150° C., 0.5 mmHg). Analysiscalculated for C₁₀ H₁₄ NO₃ Cl_(3:)

C: 39.69H: 4.66N: 4.64 Found: C:39.87H: 4.62N:4.49

STEP E: 4-AMINO-5-HEXENOIC ACID:

A suspension of ethyl 4-trichloroacetoamido-5-hexenoate (0.3 g, 1 mmol)in 6N HCl (10 mL) was heated under reflux 6H. Then the mixture wasconcentrated in, vacuo, diluted with water (10 mL), washed twice withAcoet, and dried in vacuo to give the title product (0.18 g, 100%). NMR,TLC (NH₄ OH:EtOH, 3:7) are identical with those of an authentic sampleof 4-amino-5hexenoic acid. ¹ H NMR (90 MHz) (D₂), δ ppm. (TMS) 1.83 (m,2H, CH₂ CO₂), 2.33 (m, 2H, CH₂ CH₂) 3.66 (m, 1H, CH--C═), 5.35 (m, 3H,CH₂ ═CH) .

What is claimed is:
 1. [4]Ethyl-4-trichloroacetamido-4-hexenoate.